Cognitive decline associated with aging and Alzheimer's disease (AD) is among the most common and debilitating conditions, and poses a large and increasing public health problem. Projections indicate that the prevalence of aging-related chronic conditions is expected to increase substantially in the next decade. This will be particularly true for minority populations, especially the older African American population, which is growing at an even more rapid pace than the older White population. The Minority Aging Research Study (MARS) is a longitudinal cohort study of more than 350 older African Americans without dementia who agreed to annual clinical evaluations. During the previous project period we identified several risk factors for cognitive decline in African Americans. The overall goal of the proposed continuation is to quantify three common neuropathologic indices including Alzheimer's disease pathology, cerebral infarctions, and Lewy bodies in MARS participants, and examine their associations to cognitive function and clinical risk factors. In addition, to increase power and examine racial differences in these associations, we propose to use existing longitudinal clinical and neuropathologic data on Whites from two other ongoing cohort studies at Rush. Our Specific Aims are to: 1) examine the association of the three post-mortem neuropathologic indices to 1a: level of global cognition and five cognitive abilities, 1b: change in global cognition and five cognitive abilities; 2) examine racial differences in the associations of neuropathology to level of and change in cognitive function; 3) test the hypothesis that the APOE e4 allele is associated with increased levels of AD pathology, and the 52 allele is associated with a lower level of AD pathology in African Americans; and 4) examine the relationship of BMI to neuropathology, and test the hypothesis that BMI is more strongly associated with AD pathology in Whites than in African Americans. There is limited data on the neuropathologic basis of cognitive impairment in African Americans. Integrating post-mortem indices into a study of risk factors for cognitive decline in one of the fastest growing minority groups is highly innovative and has the potential to greatly increase understanding of the ways in which risk factors interact with neuropathology to influence cognition and racial disparities in cognitive test performance. Further, the findings could have important implications for therapeutic intervention and disease prevention. PUBLIC HEALTH RELEVANCE: This project will examine the association of Alzheimer disease pathology and other common neuropathologic indices on risk factors and change in cognitive function over time in older African Americans. An important strength of the study is that it will take advantage of the availability of detailed information on cognitive function and biological and clinical risk factors of interest from the prior project period and supplement it with quantitative postmortem measurements on more than 100 African Americans. Findings from this study are expected to provide a better understanding of the extent to which neuropathologic indices contribute to cognitive impairment in African Americans, and how pathology may interact with important risk factors to effect racial differences in cognitive function.